Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis

Jing Wang, Karen Kuropatwinski, Jennie Hauser, Michael R. Rossi, Yunfei Zhou, Alexis Conway, Julie L.C. Kan, Neil W. Gibson, James K.V. Willson, John K. Cowell, Michael G Brattain

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

PIK3CA, encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is mutated in a variety of human cancers. We screened the colon cancer cell lines previously established in our laboratory for PIK3CA mutations and found that four of them harbored gain of function mutations. We have now compared a panel of mutant and wild-type cell lines for cell proliferation and survival in response to stress. There was little difference in PI3K activity between mutant PIK3CA-bearing cells (mutant cells) and wild-type PIK3CA-bearing cells (wild-type cells) under optimal growth conditions. However, the mutant cells showed constitutive PI3K activity during growth factor deprivation stress (GFDS), whereas PI3K activity decayed rapidly in the wild-type cells. Importantly, constitutively active PI3K rendered the mutant cells resistant to GFDS-induced apoptosis relative to the wild-type cells, indicating a biological advantage under stress conditions that is imparted by the mutant enzymes. Compared with the wild-type cells, the mutant cells were hypersensitive to the apoptosis induced by the PI3K inhibitor LY294002. In addition, PIK3CA small interfering RNA significantly decreased DNA synthesis and/or induced apoptosis in the mutant cells but not in the wild-type cells. Furthermore, ecotopic expression of a mutant PIK3CA in a nontumorigenic PIK3CA wild-type cell line resulted in resistance to GFDS-induced apoptosis, whereas transfection of wild-type PIK3CA or empty vector had little effect. Taken together, our studies show that mutant PIK3CA increases the capacity for proliferation and survival under environmental stresses, such as GFDS while also imparting greater dependency on the PI3K pathway for proliferation and survival.

Original languageEnglish (US)
Pages (from-to)1143-1150
Number of pages8
JournalMolecular cancer therapeutics
Volume6
Issue number3
DOIs
StatePublished - Mar 1 2007

Fingerprint

Phosphatidylinositol 3-Kinase
Intercellular Signaling Peptides and Proteins
Colon
Apoptosis
Carcinoma
Mutation
Cell Line
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Colonic Neoplasms
Small Interfering RNA
Transfection
Catalytic Domain
Cell Survival
Cell Proliferation
Survival
DNA
Enzymes
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, J., Kuropatwinski, K., Hauser, J., Rossi, M. R., Zhou, Y., Conway, A., ... Brattain, M. G. (2007). Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis. Molecular cancer therapeutics, 6(3), 1143-1150. https://doi.org/10.1158/1535-7163.MCT-06-0555

Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis. / Wang, Jing; Kuropatwinski, Karen; Hauser, Jennie; Rossi, Michael R.; Zhou, Yunfei; Conway, Alexis; Kan, Julie L.C.; Gibson, Neil W.; Willson, James K.V.; Cowell, John K.; Brattain, Michael G.

In: Molecular cancer therapeutics, Vol. 6, No. 3, 01.03.2007, p. 1143-1150.

Research output: Contribution to journalArticle

Wang, J, Kuropatwinski, K, Hauser, J, Rossi, MR, Zhou, Y, Conway, A, Kan, JLC, Gibson, NW, Willson, JKV, Cowell, JK & Brattain, MG 2007, 'Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis', Molecular cancer therapeutics, vol. 6, no. 3, pp. 1143-1150. https://doi.org/10.1158/1535-7163.MCT-06-0555
Wang, Jing ; Kuropatwinski, Karen ; Hauser, Jennie ; Rossi, Michael R. ; Zhou, Yunfei ; Conway, Alexis ; Kan, Julie L.C. ; Gibson, Neil W. ; Willson, James K.V. ; Cowell, John K. ; Brattain, Michael G. / Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis. In: Molecular cancer therapeutics. 2007 ; Vol. 6, No. 3. pp. 1143-1150.
@article{8fb8babcf4b54e4699903ec3484d5ce7,
title = "Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis",
abstract = "PIK3CA, encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is mutated in a variety of human cancers. We screened the colon cancer cell lines previously established in our laboratory for PIK3CA mutations and found that four of them harbored gain of function mutations. We have now compared a panel of mutant and wild-type cell lines for cell proliferation and survival in response to stress. There was little difference in PI3K activity between mutant PIK3CA-bearing cells (mutant cells) and wild-type PIK3CA-bearing cells (wild-type cells) under optimal growth conditions. However, the mutant cells showed constitutive PI3K activity during growth factor deprivation stress (GFDS), whereas PI3K activity decayed rapidly in the wild-type cells. Importantly, constitutively active PI3K rendered the mutant cells resistant to GFDS-induced apoptosis relative to the wild-type cells, indicating a biological advantage under stress conditions that is imparted by the mutant enzymes. Compared with the wild-type cells, the mutant cells were hypersensitive to the apoptosis induced by the PI3K inhibitor LY294002. In addition, PIK3CA small interfering RNA significantly decreased DNA synthesis and/or induced apoptosis in the mutant cells but not in the wild-type cells. Furthermore, ecotopic expression of a mutant PIK3CA in a nontumorigenic PIK3CA wild-type cell line resulted in resistance to GFDS-induced apoptosis, whereas transfection of wild-type PIK3CA or empty vector had little effect. Taken together, our studies show that mutant PIK3CA increases the capacity for proliferation and survival under environmental stresses, such as GFDS while also imparting greater dependency on the PI3K pathway for proliferation and survival.",
author = "Jing Wang and Karen Kuropatwinski and Jennie Hauser and Rossi, {Michael R.} and Yunfei Zhou and Alexis Conway and Kan, {Julie L.C.} and Gibson, {Neil W.} and Willson, {James K.V.} and Cowell, {John K.} and Brattain, {Michael G}",
year = "2007",
month = "3",
day = "1",
doi = "10.1158/1535-7163.MCT-06-0555",
language = "English (US)",
volume = "6",
pages = "1143--1150",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis

AU - Wang, Jing

AU - Kuropatwinski, Karen

AU - Hauser, Jennie

AU - Rossi, Michael R.

AU - Zhou, Yunfei

AU - Conway, Alexis

AU - Kan, Julie L.C.

AU - Gibson, Neil W.

AU - Willson, James K.V.

AU - Cowell, John K.

AU - Brattain, Michael G

PY - 2007/3/1

Y1 - 2007/3/1

N2 - PIK3CA, encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is mutated in a variety of human cancers. We screened the colon cancer cell lines previously established in our laboratory for PIK3CA mutations and found that four of them harbored gain of function mutations. We have now compared a panel of mutant and wild-type cell lines for cell proliferation and survival in response to stress. There was little difference in PI3K activity between mutant PIK3CA-bearing cells (mutant cells) and wild-type PIK3CA-bearing cells (wild-type cells) under optimal growth conditions. However, the mutant cells showed constitutive PI3K activity during growth factor deprivation stress (GFDS), whereas PI3K activity decayed rapidly in the wild-type cells. Importantly, constitutively active PI3K rendered the mutant cells resistant to GFDS-induced apoptosis relative to the wild-type cells, indicating a biological advantage under stress conditions that is imparted by the mutant enzymes. Compared with the wild-type cells, the mutant cells were hypersensitive to the apoptosis induced by the PI3K inhibitor LY294002. In addition, PIK3CA small interfering RNA significantly decreased DNA synthesis and/or induced apoptosis in the mutant cells but not in the wild-type cells. Furthermore, ecotopic expression of a mutant PIK3CA in a nontumorigenic PIK3CA wild-type cell line resulted in resistance to GFDS-induced apoptosis, whereas transfection of wild-type PIK3CA or empty vector had little effect. Taken together, our studies show that mutant PIK3CA increases the capacity for proliferation and survival under environmental stresses, such as GFDS while also imparting greater dependency on the PI3K pathway for proliferation and survival.

AB - PIK3CA, encoding the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is mutated in a variety of human cancers. We screened the colon cancer cell lines previously established in our laboratory for PIK3CA mutations and found that four of them harbored gain of function mutations. We have now compared a panel of mutant and wild-type cell lines for cell proliferation and survival in response to stress. There was little difference in PI3K activity between mutant PIK3CA-bearing cells (mutant cells) and wild-type PIK3CA-bearing cells (wild-type cells) under optimal growth conditions. However, the mutant cells showed constitutive PI3K activity during growth factor deprivation stress (GFDS), whereas PI3K activity decayed rapidly in the wild-type cells. Importantly, constitutively active PI3K rendered the mutant cells resistant to GFDS-induced apoptosis relative to the wild-type cells, indicating a biological advantage under stress conditions that is imparted by the mutant enzymes. Compared with the wild-type cells, the mutant cells were hypersensitive to the apoptosis induced by the PI3K inhibitor LY294002. In addition, PIK3CA small interfering RNA significantly decreased DNA synthesis and/or induced apoptosis in the mutant cells but not in the wild-type cells. Furthermore, ecotopic expression of a mutant PIK3CA in a nontumorigenic PIK3CA wild-type cell line resulted in resistance to GFDS-induced apoptosis, whereas transfection of wild-type PIK3CA or empty vector had little effect. Taken together, our studies show that mutant PIK3CA increases the capacity for proliferation and survival under environmental stresses, such as GFDS while also imparting greater dependency on the PI3K pathway for proliferation and survival.

UR - http://www.scopus.com/inward/record.url?scp=34147172885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34147172885&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-06-0555

DO - 10.1158/1535-7163.MCT-06-0555

M3 - Article

VL - 6

SP - 1143

EP - 1150

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 3

ER -